The present invention relates to methods and pharmaceutical compositions for An treating and preventing alopecia in a a patient in need thereof.
Hair growth is not continuous, but comprises alternating periods of growth (xe2x80x9canagenxe2x80x9d), regression (xe2x80x9ccategenxe2x80x9d) and rest (xe2x80x9ctelogenxe2x80x9d). (U.S. Pat. No. 5,055,456, incorporated by reference herein in its entirety) In the scalp, the anagen phase lasts about 6 years and the telogen phase about 4 months. The growth of scalp hair is not synchronous, and the rate of growth is about 0.4 mm per day. About 90 percent of the more than 100,000 scalp hairs are growing (anagen), so that 50 to 100 hairs are shed daily as they are pushed out at the onset of a new hair cycle.
The hair follicle is an epidermal appendage, the lower part of which undergoes cycles of growth and degeneration. (U.S. Pat. No. 5,556,783, incorporated by reference herein in its entirety) During the anagen (the growing phase) of the hair cycle, matrix keratinocytes located in the bulb region grow vigorously, generating cells that differentiate into several distinct hair components including the medulla, cortex and inner root sheath. During catagen, keratinocytes of the lower follicle below the bulge region (the attachment site of the arrector pili muscle) degenerate and the dermal papilla cells (DP; a group of specialized mesenchymal cells) aggregate and become encapsulated by a connective tissue sheath. Through the contraction of this sheath, the DP aggregate ascends and becomes attached to the bottom of the upper (permanent) portion of the follicle (telogen or the resting phase). Finally, a new epithelial growth originates from the bottom of the bulge area; this downgrowth pushes the DP away and reforms a growing bulb.
The in vitro growth potential of different subpopulations of follicular epithelial cells have been studied. (U.S. Pat. No. 5,556,783) Keratinocytes of different portions of human scalp follicles were isolated by microdissection followed by trypsinization and propagated in the presence of 3T3 feeder cells. The results indicate that the upper follicle contains keratinocytes that have in vitro proliferative potential that is significantly higher than those of the lower follicle, the bulb, the sebaceous gland and the epidermis.
Alopecia (hair loss) is a common condition that results from diverse causes. For example, adrenergic alopecia (common baldness) is seen in the vast majority of adult males and is considered physiologic and part of the aging process. (U.S. Pat. No. 5,616,471, incorporated by reference herein in its entirety) Besides the loss of hair, the length and diameter of each hair will be reduced in the adjacent areas even though the follicles remain intact.
Telogen effluvium is a transient, reversible, diffuse shedding of hair in which a high percentage of hair follicles enter the telogen phase prematurely as a result of physical or mental illness. Among the most important factors incriminated are childbirth, high fever, hemorrhage, sudden starvation, accidental or surgical trauma, severe emotional stress, and certain drugs.
Alopecia areata is an immunologic alopecia characterized by the abrupt onset of sharply defined areas of hair loss. In the most severe cases, the scalp will develop total hair loss (alopecia totalis) or the hair loss will involve the whole body surface (alopecia universalis). Most of the patients will run an unpredictable and relapsing course with multiple episodes of hair loss and regrowth. Only about 20 to 30 percent will have a single reversible episode. Regrowth of hair is common within several months, but in many instances is not complete, and relapses are common. Alopecia areata may be associated with autoimmune diseases such as vitiligo, pernicious anemia, collagen disease, and endocrinopathies.
Traumatic alopecia is induced by physical trauma, of which the two most important groups, from the therapeutic standpoint are trichotillomania and alopecia resulting from cosmetic procedures or improper hair care. Trichotillomania is a compulsive habit in which the individual repeatedly pulls or breaks off his or her own hair in a partially conscious state similar to thumb sucking or nail biting. Traumatic alopecia from cosmetic procedures is done consciously in ill-advised individuals and is almost exclusively seen among females. Sometimes this type of alopecia is associated with folliculitis induced by the occlusive effect of the oily cosmetics used in the procedure.
Anagen effluvium is a temporary alopecia caused by the inhibition of mitosis in the hair papilla by certain cytotoxic drugs, leading to constriction of the hair shaft or to complete failure of hair formation. In particular, alopecia frequently occurs in cancer patients who are treated with chemotherapeutic drugs such as cyclophosphamide (CY) and/or irradiation. U.S. Pat. No. 5,962,523 Such agents damage hair follicles which contain mitotically active hair-producing cells. Such damage may cause abnormally slow growth of the hair or may lead to frank loss. While various attempts have been made to protect against alopecia or abnormal rates of hair growth during such treatments, there remains a need for an agent that prevents damage to hair follicles in a safe and effective manner.
Alopecia may also result from nutritional deficiencies and metabolic defects. Caloric deprivation must be very severe to produce hair loss. Increased shedding sometimes occurs after marked weight loss for obesity. Anemia, diabetes, hyper- and hypovitaminosis, and zinc deficiency may also lead to alopecia.
Treatments for androgenetic alopecia have been ineffective in inducing regrowth. The use of cyclic estrogen therapy in females with an estrogen-dominant contraceptive or topical estrogen has been advocated to reduce the rate of hair loss, but results are not impressive. The claim that topical testosterone induces the growth of terminal hairs in bald scalp of males has not been confirmed.
There have been some indications that minoxidil (ROGAINE(copyright)., Upjohn), a potent vasodilator, has been effective in causing scalp hair regrowth in patients with androgenetic alopecia, but the results have been mixed.
U.S. Pat. 5,962,523 discloses the use of butyric acid or butyric acid derivatives to protect against hair damage or loss in a mammal as described herein.
Thus, there remains a need in the art for methods of treating and preventing the various types of alopecia.
In one aspect, the present invention provides methods and kits for treating or preventing alopecia by contacting the cells with angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II (AII), AII analogues, AII fragments or analogues thereof, ACE inhibitors, or AII AT2 type 2 receptor agonists, either alone or in combination with other alopecia-inhibiting compounds.